Pharmacokinetics and pharmacodynamics of candesartan after administration of its pro-drug candesartan cilexetil in patients with mild to moderate essential hypertension--a population analysis.
OBJECTIVE
The pharmacokinetics and pharmacodynamics of the angiotensin (AT) II receptor, AT1-subtype, antagonist candesartan were investigated in a dose-finding study in 232 patients of either gender, aged 28-69 years and weighing 54-110 kg. The study was a double-blind, placebo-controlled trial in which oral doses of 2, 4, 8, 12 and 16 mg once daily were given as the pro-drug candesartan cilexetil from day 0 to day 28.


RESULTS
The population pharmacokinetics of candesartan could be best described by a two-compartment body model, parameterized in terms of clearance (14.1 1.h-1), central volume of distribution (118 1), peripheral volume (272 1) and intercompartmental clearance (15.4 1.h-1). From these model parameters, a cumulation half-life (t1/2, beta) of 29 h was derived. Age and weight were influencing factors for the distribution and elimination of the drug. Systolic and diastolic blood pressure were lowered by the treatment in a dose-dependent fashion. The maximum effect of each dose was reached after repeated administration. The link between plasma concentrations and effect could be described by a linear model when trough concentrations and blood pressure, measured at the same time, were modelled. In this model, the time dependence is implicitly handled as the trough concentrations increased during repeated administration. After treatment with the highest dose used in the trial (16 mg), the population estimate for the diastolic blood pressure was reduced from 103.2 mmHg (pre-dose day 0) to 93.3 mmHg (on day 29) and the systolic blood pressure from 154.6 mmHg (pre-dose day 0) to 137.9 mmHg (on day 29). None of the covariates (age, weight, gender) had an influence on the concentration-effect relationship.
Meineke
I
I
Department of Clinical Pharmacology, University of Göttingen, Germany.
Feltkamp
H
H
Högemann
A
A
Gundert-Remy
U
U
D000328:Adult; D000368:Aged; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000493:pharmacokinetics*; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011355:Prodrugs; D013777:Tetrazoles; C077793:candesartan cilexetil